Weight gain does more than expand one’s waistline and limit one’s wardrobe. In fact, if obesity persists into the chronic phase it contributes to metabolic inflammatory disorders, such as type 2 diabetes and cardiovascular disease. Although members of the interleukin-1 (IL-1) cytokine family orchestrate chronic and acute proinflammatory responses, one sibling, IL-37, recently was shown to display anti-inflammatory properties in both acute and chronic models of inflammation. Whether IL-37 dampens chronic low-grade inflammation in the context of obesity is unknown. Now, Ballack et al. show that when transgenic mice that are engineering to express human IL-37 are fed a high-fat diet (HFD), they exhibit a reduction in weight gain, lower adipocyte mass and size, less adipose tissue inflammation, and less insulin resistance than do HFD-fed wild-type obese mice. Furthermore, treatment of the wild-type mice with recombinant IL-37 yielded effects similar to those observed in animals that express the human IL-37 gene.

Using the IL-37 transgenic mice, the authors investigated molecular programs involved in the IL-37–mediated increase in insulin sensitivity and found that the cytokine preserved insulin receptor substrate–1 tyrosine phosphorylation, thus rescuing insulin signaling in human HepG2 hepatoma cells. Next, the authors investigated IL-37 expression in various tissues from a cohort of obese people and its connection with markers of metabolic states. ​IL-37 expression in human adipose tissue was inversely correlated with adipose tissue inflammation and the presence of insulin resistance. As humans reveal an inverse correlation between inflammation in adipose tissue and expression of IL-37, it is possible that subjects who fail to express sufficient IL-37 locally will develop higher levels of inflammation. Thus, these data support a link between ​IL-37 biology, adipose tissue inflammation, and insulin sensitivity.

Although the in vivo source of IL-37 is unknown and the lack of mouse homolog makes mechanistic studies difficult, the new work highlights regulatory mechanisms involved in the maintenance of chronic metabolic diseases. More work is needed to assess whether IL-37 can serve as a therapy to reduce adipose tissue inflammation in obese people and perhaps alleviate the damaging effects of obesity-induced insulin resistance and type 2 diabetes.